Abstract: SA-PO599
Targeting Enhancer of Zeste Homolog 2 Protects Against AKI
Session Information
- AKI: Other Mechanisms and Cell Cultures
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhou, Xiaoxu, Rhode Island Hospital, Brown University, Providence, Rhode Island, United States
- Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
Background
Despite the established oncogenic and profibrotic functions of enhancer of zeste homolog 2 (EZH2), a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3), its role in acute kidney injury (AKI) remains unclear.
Methods
In this study, we examined the effect of EZH2 inhibition on acute kidney injury in murine models induced by induced by either ischemia-reperfusion (IR) or folic acid (FA).
Results
We demonstrated that EZH2 and H3K27me3 were upregulated in the murine kidney with AKI in both models. Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) inhibited tubular injury in both models as demonstrated by a decrease in renal dysfunction, reduced neutrophil gelatinase-associated lipocalin expression and a lower rate of renal tubule cell death. Injury to the kidney resulted in reduced expression of E-cadherin and ZO-1, whereas EZH2 inhibition largely preserved their expression. Moreover, 3-DZNep was effective in counteracting the increased expression of matrix metalloproteinase (MMP) -2 and -9 as well as the phosphorylation of Raf-1 and ERK1/2 in the injured kidney. Conversely, blocking EZH2 reversed the decrease of tissue inhibitor of metalloproteinase (TIMP)-2 and -3 and Raf kinase inhibitor protein (RKIP) in the kidney after acute injury. Similarly, oxidant injury to cultured kidney proximal tubular epithelial cells caused a decrease in the expression of E-cadherin, ZO-1, TIMP-2/-3, and RKIP as well as an increase in the expression of MMP-2/9 and phosphorylation of Raf-1 ERK1/2. Blocking EZH2 with 3-DZNep or SiRNA hindered these responses.
Conclusion
These results suggest that targeting EZH2 protects against AKI through a mechanism associated with the preservation of adhesion/junctions, reduction of matrix metalloproteinases and attenuation of the Raf-1/ERK1/2 pathway.
Funding
- NIDDK Support